EP2494400A1 - Imagerie de microscopie - Google Patents
Imagerie de microscopieInfo
- Publication number
- EP2494400A1 EP2494400A1 EP10827423A EP10827423A EP2494400A1 EP 2494400 A1 EP2494400 A1 EP 2494400A1 EP 10827423 A EP10827423 A EP 10827423A EP 10827423 A EP10827423 A EP 10827423A EP 2494400 A1 EP2494400 A1 EP 2494400A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- specimen
- light
- light source
- chamber
- imaging
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000003384 imaging method Methods 0.000 title claims abstract description 99
- 238000000386 microscopy Methods 0.000 title description 13
- 239000012530 fluid Substances 0.000 claims description 46
- 239000000463 material Substances 0.000 claims description 24
- 239000007788 liquid Substances 0.000 claims description 17
- 239000000523 sample Substances 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 13
- 239000003251 chemically resistant material Substances 0.000 claims description 12
- 238000000576 coating method Methods 0.000 claims description 12
- 239000011248 coating agent Substances 0.000 claims description 10
- 239000000853 adhesive Substances 0.000 claims description 9
- 230000001070 adhesive effect Effects 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 5
- 229910003460 diamond Inorganic materials 0.000 claims description 4
- 239000010432 diamond Substances 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 3
- 229910052581 Si3N4 Inorganic materials 0.000 claims description 2
- 230000003287 optical effect Effects 0.000 description 19
- 238000005286 illumination Methods 0.000 description 15
- 239000000758 substrate Substances 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 9
- 230000005540 biological transmission Effects 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 7
- 239000004033 plastic Substances 0.000 description 7
- 229920003023 plastic Polymers 0.000 description 7
- 238000003860 storage Methods 0.000 description 7
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 6
- 238000003491 array Methods 0.000 description 6
- 229910052751 metal Inorganic materials 0.000 description 6
- 239000002184 metal Substances 0.000 description 6
- 229910052710 silicon Inorganic materials 0.000 description 6
- 239000010703 silicon Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 230000008901 benefit Effects 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 230000003595 spectral effect Effects 0.000 description 5
- 241000269368 Xenopus laevis Species 0.000 description 4
- 239000011324 bead Substances 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 229910000679 solder Inorganic materials 0.000 description 4
- 239000010409 thin film Substances 0.000 description 4
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 3
- 238000005229 chemical vapour deposition Methods 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000000399 optical microscopy Methods 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 229920001621 AMOLED Polymers 0.000 description 2
- 229920002799 BoPET Polymers 0.000 description 2
- 239000005041 Mylar™ Substances 0.000 description 2
- 239000004793 Polystyrene Substances 0.000 description 2
- 229920005654 Sephadex Polymers 0.000 description 2
- 239000012507 Sephadex™ Substances 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000002083 X-ray spectrum Methods 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 230000003416 augmentation Effects 0.000 description 2
- 238000001444 catalytic combustion detection Methods 0.000 description 2
- 239000000919 ceramic Substances 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 239000011152 fibreglass Substances 0.000 description 2
- 238000000684 flow cytometry Methods 0.000 description 2
- 230000004907 flux Effects 0.000 description 2
- 230000005484 gravity Effects 0.000 description 2
- 230000033001 locomotion Effects 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 239000002086 nanomaterial Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 238000002161 passivation Methods 0.000 description 2
- 230000010287 polarization Effects 0.000 description 2
- 229920002223 polystyrene Polymers 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 230000002123 temporal effect Effects 0.000 description 2
- 239000012780 transparent material Substances 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- IRPGOXJVTQTAAN-UHFFFAOYSA-N 2,2,3,3,3-pentafluoropropanal Chemical compound FC(F)(F)C(F)(F)C=O IRPGOXJVTQTAAN-UHFFFAOYSA-N 0.000 description 1
- KLZUFWVZNOTSEM-UHFFFAOYSA-K Aluminum fluoride Inorganic materials F[Al](F)F KLZUFWVZNOTSEM-UHFFFAOYSA-K 0.000 description 1
- JBRZTFJDHDCESZ-UHFFFAOYSA-N AsGa Chemical compound [As]#[Ga] JBRZTFJDHDCESZ-UHFFFAOYSA-N 0.000 description 1
- 241000238571 Cladocera Species 0.000 description 1
- 241000238578 Daphnia Species 0.000 description 1
- 241001494253 Daphnia sp. Species 0.000 description 1
- 229910002601 GaN Inorganic materials 0.000 description 1
- 229910001218 Gallium arsenide Inorganic materials 0.000 description 1
- JMASRVWKEDWRBT-UHFFFAOYSA-N Gallium nitride Chemical compound [Ga]#N JMASRVWKEDWRBT-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 238000001069 Raman spectroscopy Methods 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 238000000376 autoradiography Methods 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000009087 cell motility Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 230000001010 compromised effect Effects 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000001446 dark-field microscopy Methods 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000009795 derivation Methods 0.000 description 1
- 230000001066 destructive effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- -1 droplets Substances 0.000 description 1
- 230000005684 electric field Effects 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 239000005350 fused silica glass Substances 0.000 description 1
- 229910052732 germanium Inorganic materials 0.000 description 1
- GNPVGFCGXDBREM-UHFFFAOYSA-N germanium atom Chemical compound [Ge] GNPVGFCGXDBREM-UHFFFAOYSA-N 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000010191 image analysis Methods 0.000 description 1
- 238000003702 image correction Methods 0.000 description 1
- 238000003707 image sharpening Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 239000011810 insulating material Substances 0.000 description 1
- 239000012212 insulator Substances 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000004816 latex Substances 0.000 description 1
- 229920000126 latex Polymers 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- ORUIBWPALBXDOA-UHFFFAOYSA-L magnesium fluoride Chemical compound [F-].[F-].[Mg+2] ORUIBWPALBXDOA-UHFFFAOYSA-L 0.000 description 1
- 229910001635 magnesium fluoride Inorganic materials 0.000 description 1
- 238000001755 magnetron sputter deposition Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 229910044991 metal oxide Inorganic materials 0.000 description 1
- 150000004706 metal oxides Chemical class 0.000 description 1
- 239000011325 microbead Substances 0.000 description 1
- 238000002044 microwave spectrum Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 238000004651 near-field scanning optical microscopy Methods 0.000 description 1
- 239000000615 nonconductor Substances 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- BPUBBGLMJRNUCC-UHFFFAOYSA-N oxygen(2-);tantalum(5+) Chemical compound [O-2].[O-2].[O-2].[O-2].[O-2].[Ta+5].[Ta+5] BPUBBGLMJRNUCC-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 239000006223 plastic coating Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 238000004886 process control Methods 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 239000004065 semiconductor Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- HQVNEWCFYHHQES-UHFFFAOYSA-N silicon nitride Chemical compound N12[Si]34N5[Si]62N3[Si]51N64 HQVNEWCFYHHQES-UHFFFAOYSA-N 0.000 description 1
- 229910052814 silicon oxide Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 229910001936 tantalum oxide Inorganic materials 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- BYMUNNMMXKDFEZ-UHFFFAOYSA-K trifluorolanthanum Chemical compound F[La](F)F BYMUNNMMXKDFEZ-UHFFFAOYSA-K 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000001429 visible spectrum Methods 0.000 description 1
- 238000004876 x-ray fluorescence Methods 0.000 description 1
Classifications
-
- G—PHYSICS
- G02—OPTICS
- G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
- G02B21/00—Microscopes
- G02B21/0004—Microscopes specially adapted for specific applications
- G02B21/0008—Microscopes having a simple construction, e.g. portable microscopes
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2201/00—Features of devices classified in G01N21/00
- G01N2201/06—Illumination; Optics
- G01N2201/061—Sources
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2201/00—Features of devices classified in G01N21/00
- G01N2201/06—Illumination; Optics
- G01N2201/061—Sources
- G01N2201/0616—Ambient light is used
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2201/00—Features of devices classified in G01N21/00
- G01N2201/06—Illumination; Optics
- G01N2201/062—LED's
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2201/00—Features of devices classified in G01N21/00
- G01N2201/06—Illumination; Optics
- G01N2201/063—Illuminating optical parts
Definitions
- Microscopy in its various forms is an essential tool in an ever-growing range of human activity, from basic research in the natural sciences, industrial research and development, process and quality control, forensics and biosafety, to clinical human and veterinary medical diagnostics, among others.
- the most widely used form of microscopy is optical.
- the resolution of standard forms of optical microscopy is limited to several hundred nanometers by the diffraction of light between the specimen and the microscope objective lens. Due to its wave properties, light passing through a circular lens creates a ring-shaped diffraction pattern; the images of two different points formed by such a lens can be resolved if the principal diffraction maximum of one point lies outside of the first minimum of the other point.
- This theoretical diffraction limit also known as the Abbe limit or Rayleigh criterion, is approximately equal to 0.61 X I NA, where ⁇ is the wavelength of the light and NA is the numerical aperture of the lens, given by
- NA n sin a
- n is the index of refraction of the optical medium between the lens and the specimen and a is the half-angle of acceptance of the lens.
- a is the half-angle of acceptance of the lens.
- NA can be increased by use of high refractive index media.
- the size of an illumination spot can be reduced by strategies such as stimulated emission depletion (STED), or the positions of sparse individual molecules can be approximated by the centers of their diffracted images.
- NSMs Near-field scanning optical microscopes
- a probe having a tip smaller than the wavelength of light and positioned less than a wavelength from the specimen.
- the probe tip or aperture is scanned along the specimen close to its surface to map the near field produced by fluorescence at the specimen surface.
- NSOM imaging is non-destructive and can be carried out in an aqueous environment, permitting obsen'ation of living cells and hydrated molecules.
- Lensless microscopy methods are known, however they may require integration of multiple images or subsequent computational image derivation in order to produce usable images.
- an imaging device has a photosensitive array of pixels, and a surface associated with the array is configured to receive a specimen with at least a part of the specimen at a distance from the surface equivalent to less than about half of an average width of the pixels.
- the specimen is included. There is a light source. A specimen chamber adjacent the surface is defined in part by a wall that is spaced apart from the surface and transmits light to illuminate the specimen. A fluid channel carries a fluid specimen into the chamber. The chamber is sealed against leakage of fluid. A second fluid channel carries the fluid specimen out of the chamber. There is a reservoir for the fluid specimen and a pump to pump the fluid specimen from the reservoir and into and out of the chamber. There is an imaging integrated circuit. The integrated circuit is back-side illuminated. A computer-based system uses a program to display, analyze, or store high-resolution images of the specimen using information derived from the device.
- the specimen comprises a solid.
- the specimen comprises a liquid or is suspended or dissolved in a liquid.
- the wall has at least one electrode adjacent to the chamber.
- the wall has a heating element adjacent to the chamber.
- the wall has a temperature probe adjacent to the chamber.
- the wall has a pH probe adjacent to the chamber.
- the wall is at least partially translucent.
- the light source is positioned so that a path of light from the light source to the surface is at an angle of 45 degrees or more to the surface.
- the light source is positioned so that a path of light from the light source to the surface is at an angle of at most 45 degrees to the surface.
- the light source is positioned so that a path of light from the light source to the surface is approximately parallel to the surface.
- the light source comprises light-emitting diodes.
- the light source comprises ambient light.
- the light source comprises a portable multi-color light source.
- the chemically resistant material comprises diamond.
- the chemically resistant material comprises AI2O3.
- the chemically resistant material comprises S13N4.
- a layer of light-transmissive material contains fluorophores on the surface. The specimen emits light.
- a layer of adhesive material coats the surface.
- the photosensitive array provides a high resolution.
- an imaging device has a photosensitive array, and a surface associated with the array is configured to receive a specimen with at least a part of the specimen at a distance from the photosensitive array that satisfies or at least approximately satisfies a near-field criterion.
- At least a part of a specimen is placed at a distance, from a surface associated with a photosensitive array of pixels, that is equivalent to less than about half of an average width of the pixels, and signals generated by the photosensitive array are used to produce a high resolution image of the specimen.
- FIG. 1 shows a top view of an imaging device.
- FIG. 2 shows a section view of an imaging device.
- FIG. 3 shows a top view of an imaging integrated circuit.
- FIG. 4 shows a section view of an imaging device equipped with a light source, a probe, electrodes, a heating element, and a fluid flow system.
- FIGs. 5A, 5B, and 5C show section views of an imaging device with light sources: light-emitting diodes (FIG. 5A), ambient (FIG. 5B), and portable multi-color (FIG. 5C).
- FIGs. 6A through 6G show section views of an imaging integrated circuit with coatings: transparent, wavelength-filtering or polarizing (FIG. 6A), metallic (FIG. 6B), plastic (FIG. 6C), transparent chemically resistant (FIG. 6D), nonconductor (FIG. 6E), adhesive (FIG. 6F), and transparent having fluorophores, scintillants or phosphors (FIG. 6G).
- FIG. 7 shows a section view of an imaging device equipped with a portable multi-color light source and a housing with power, I/O, and fluid connectors.
- FIG. 8 shows a schematic of an imaging device and a computer-based system, with dashed lines indicating light along the optical path.
- FIG. 9 shows a computed plot of a pixel response due to light from a point source passing into an imaging integrated circuit constructed in silicon at various distances from a center of a middle pixel (origin) as the distance (elevation) of the source above that center is increased. Distance, both laterally and above the surface, is measured in units of the width of a pixel. Each curve represents a relation for a specified vertical distance of the source above the photosensitive surface of the imaging integrated circuit, as indicated in the inset key.
- FIGs. 10A and 10B show (10A) transmission coefficients of the Fresnel formulas for angles between zero and ninety degrees; (10B) an illustration of decreasing pixel profile with respect to a light source as angle of light with respect to the surface normal increases.
- FIG. 1 1 is an image of a 30 ⁇ - thick Mylar sheet, imaged using an apparatus referred to in the Examples, having 5.2 ⁇ x 5.2 ⁇ pixels.
- FIG. 12 is an image of micro-droplets in an aerosol of organic solvent, imaged using an apparatus referred to in the Examples, having 5.2 ⁇ x 5.2 ⁇ pixels.
- FIG. 13 is an image of a ⁇ ⁇ droplet of water with suspended Sephadex beads of sizes ranging from ⁇ 20 ⁇ to > 100 ⁇ , imaged using an apparatus referred to in the Examples, having 5.2 ⁇ x 5.2 ⁇ pixels.
- FIG. 14 is an image of a sample of fresh, living, unstained blood from an African clawed frog (Xenopus laevis), diluted in calcium-free Ringer's solution, imaged using an apparatus referred to in the Examples, with pixels 2.2 ⁇ x 2.2 ⁇ .
- a full field of view (3.2 x 2.4 mm) is shown, along with a "zoomed in" view of part of the field of view, in which the elliptical shape and nucleated structure of the erythrocytes (long axis ⁇ 24 ⁇ , short axis ⁇ 16 ⁇ ) is evident.
- the zoomed image has been enhanced by 2x2 pixel augmentation with bicubic interpolation.
- FIG. 15 is a portion of the field of view of two frames of a video sequence of a living water flea (Daphnia sp.), imaged using an apparatus referred to in the Examples, with pixels 2.2 ⁇ x 2.2 ⁇ .
- the devices and methods described here can yield high-resolution images of a specimen without the need for lenses or computational image correction. Images are captured using an imaging integrated circuit having a high-resolution photosensitive array of pixels presenting a photosensitive surface, with supporting circuitry for readout, and associated computing equipment for data processing and user interaction. Light sources may be ambient or provided in an apparatus as appropriate. For parts of the specimen within half a pixel width of the photosensitive surface, the resolution of the image is limited by the size of the pixels making up the photosensitive surface.
- the near-field criterion may be satisfied and images can be obtained that equal or exceed the resolution of standard lens-based optical microscopes.
- the near-field criterion may be considered to be reached, for example, when the distance between the photosensitive surface and the specimen is less than the wavelength of interest.
- Embodiments of imaging devices are illustrated by the examples shown in Figures 1 , 2, 3, 4, 5, 6, 7 and 8.
- the imaging device may be oriented such that specimens are brought closer to the photosensitive surface by the force of gravity.
- the imaging device is inverted or mounted on its side vertically, incorporating when necessary a restraint (not shown) for specimens in the specimen chamber.
- a cavity denoted specimen chamber 101 is formed by a chamber lid 103 having walls 105 and top 107, and by a photosensitive surface 1 11 presented by an imaging integrated circuit 1 13.
- the chamber lid may be made of any material that is rigid enough to resist warping or cracking under pressure.
- the chamber lid 103 is at least partially transmissive of light.
- the walls 105 are made of opaque material (examples include metal and ceramic) and the top 107 is either absent or made of transparent material.
- the chamber lid 103 is made of glass or polystyrene and the top is between about 0.5 mm and about 1 mm in thickness.
- the walls of the chamber lid are of such dimensions and thickness as to approximately enclose the photosensitive surface in their inside dimensions and to approximately enclose the imaging integrated circuit in their outside dimensions.
- the walls of the chamber lid are rectangular and each wall of the chamber lid has an inside length less than about 10 mm.
- the distance between the top 107 of the chamber lid 103 and the surface 1 1 1 is preferably between about 50 ⁇ and about 1 mm, more preferably between about 75 ⁇ and about 250 ⁇ .
- the top 107 achieves the desired specimen chamber height in the region of a recess 1 10 with respect to the height of the walls 105; in some embodiments, the recess is either absent, or no larger than necessary to receive a light source 161.
- a surface of the bottom 109 of the chamber lid 103 may be rubberized with a gasket or treated with a water-resistant microlayer, to assure a fluid-tight pressure-resistant seal when pressed down upon the non-photosensitive ceramic or plastic package of the imaging integrated circuit 1 13 by spring clips 123.
- the specimen chamber holds the specimen and medium in which the specimen is carried.
- the medium may be air or some other gas or gas mixture appropriate to the stability or properties of the specimen.
- the medium is an appropriate liquid; the chamber need not be voided of gas in order to obtain images of such specimens.
- the imaging integrated circuit 1 13 a very-large-scale integrated (VLSI) circuit, has a high-resolution photosensitive array 203 including a two-dimensional array of pixels presented at its surface 1 1 1 , surrounded by non-photosensitive supporting circuitry 205 for readout.
- the imaging integrated circuit 1 13 (including packaging) is electrically and mechanically attached to the headboard 127, which is a printed circuit board whose components connect to circuitry on the mounting block 125.
- the imaging integrated circuit 1 13 makes electronic and mechanical connection to the headboard 127 by means of a multiplicity of solder pads 131.
- Integrated circuit packaging for such purposes includes but is not limited to ball grid arrays, quad flat packs, and leadless chip carriers.
- the array 203 is made of materials used in very-large-scale or larger integrated circuits; in some embodiments, the array is substantially germanium, gallium nitride, or gallium arsenide. In some embodiments, the array is substantially silicon.
- the high-resolution photosensitive array comprises a charge-coupled device (CCD); in other embodiments, the high-resolution
- photosensitive array is fabricated in CMOS.
- CMOS complementary metal-oxide-semiconductor
- OmniVision OV5642 imaging integrated circuit has area dimensions approximately 6.96 mm x 6.71 mm, surrounding a photosensitive array approximately 3.67 mm x 2.73 mm in area. This array is near centered, having a center with respect to the IC center (0,0) at about (220, 445) ⁇ .
- the chamber lid 103 is positioned in place within a space 1 15 defined by a rectangular locating block 1 17. Both the locating block 1 17 and the imaging integrated circuit 1 13 on its headboard 127 are situated atop the mounting block 125.
- the mounting block 125 is large enough in area to accommodate the dimensions of the locating block plus the spring clips 123.
- the locating block 1 17 is bonded to the mounting block 125 by means of solder, adhesive, or screws.
- the locating block is made of a rigid, opaque material (examples of which include plastic, metal, or fiberglass) of about 1 - 2 mm thickness, with length dimensions of at most about 0.5 mm larger than those of the chamber lid walls.
- Two or more adjacent spring clips 1 1 are bonded to mounting block 125 at their bases 124, and they overlay locating block 1 17 and at least part of the walls 105 of the chamber lid 103, holding the lid in place inside the space 1 15.
- the spring clips on each side are oriented in parallel and are of such shape as to facilitate insertion and removal of specimens and the chamber lid 103 when not in operation, but to maintain the lid in place during operation.
- the spring clips are metal.
- the spring clips are plastic.
- the chamber lid is held in the space by means of other fasteners such as, for example, screws or slides adapted to the inside of the locating block.
- the outside edge of the imaging integrated circuit 1 13 is surrounded by a rectangular shim 129 of height approximately equal to the circuit's height and thickness equal to the remainder of the space 1 15 not occupied by the imaging integrated circuit.
- the shim 129 is made of suitable shimming material; as examples, the shim can be made of plastic, phenolic, fiberglass, or metal.
- the shim 129 is bonded to the mounting block 125 by means of solder, adhesive, or screws; it is also bonded to the outside edge of the imaging integrated circuit 113 by means of injected latex, silicone, plastic (preferably polystyrene), or adhesive so as to maintain a fluid-tight seal with the imaging integrated circuit.
- One or more angled fluid channels are situated each having one lower end opening into the specimen chamber and the other, upper end positioned so as to allow flow of liquid specimen into or out of the specimen chamber, as appropriate.
- These fluid channels have diameter slightly less than the height of the specimen chamber. They are, for example, cylindrical and oriented at an angle, for example, about 45 degrees with respect to the surface 1 1 1 , permitting passage of fluid from the outside of the device into the specimen chamber.
- a fluid flow system 151 is connected to fluid channels 153, 155 by tubing 152 and respective connectors 154, 156, e.g.
- the fluid flow system 151 includes the tubing 152, a pump 157 that is preferably reversible and capable of variable flow rate, a reservoir 159, and a waste chamber 149.
- the tubing is preferably fused silica or plastic. In some embodiments, there are several pairs of fluid channels and associated fluid flow systems for flow cytometry and sorting applications.
- a specimen may be placed into the specimen chamber 101, either by temporarily removing the chamber lid 103 to give access to the specimen chamber, or, particularly in the case of liquid specimen, by inserting the liquid specimen through one of the fluid channels 153, 155.
- Liquid specimens could be blood or other cells or microorganisms, seeds, pollen, spores, particles, droplets, crystals, sediments or other materials, suspended in water, saline or other aqueous solutions, or any other sufficiently fluid and non-viscous inorganic or organic fluid.
- Such liquid specimens may be static, or can flow through the chamber during imaging, driven either by negative or positive pressure provided by a micro-pump, syringe, gravity, surface tension, rotating discs or any other suitable motive source.
- Such liquid specimens could be input using a micropipette, a syringe or another such loading device, by deposition of a droplet onto the inlet, or by connection of a fluid reservoir.
- Specimens may be, among other things, organic or inorganic, living or dead, dry or in liquid, and also combinations of those. Specimens, which depend on the resolution of the particular embodiment, can include but are not limited to proteins, DNA, RNA, nanomaterials, nanoscale structures, thin sections prepared by microtome or ultramicrotome, polymers, saccharides, lipid vesicles, biological cells, tissue samples, histological sections, micro-organisms, viruses, and combinations of those specimens. In some embodiments, seeding of a living specimen such as a cell onto the photosensitive surface or associated substrate or coating will allow for real-time or time-lapsed imaging of cell growth, movement, or other dynamic behavior. In some embodiments, specimens are stationary.
- the specimens may be caused to flow across the photosensitive surface by use of fluid channels attached to pumps and reservoirs. In some embodiments, there is at least a pair of fluid channels. In some embodiments, there are three or more fluid channels, the number being governed by the flow characteristics that are suitable for the application. In some embodiments, fluid flow is actuated by positive pressure; in some embodiments, fluid flow is actuated by negative pressure. Such an arrangement may be useful in the evaluation of disease states as imaged from cell suspensions or bodily fluids, including but not limited to blood, lymph, semen, bile, and urine. In some embodiments, the imaging integrated circuit outputs images to a computer comprising appropriate software for flow cytometry.
- placement of the specimen is manual; in the absence of a chamber lid, placing a specimen directly on the photosensitive surface will automatically satisfy or approximately satisfy the conditions for pixel-limited resolution for at least some part of the specimen; if the distance between at least part of the specimen and the photosensitive surface is less than the wavelength of light, the near-field criterion is also satisfied.
- the specimen is placed on the imaging integrated circuit or substrate using a fluid flow system for movement and flow-through imaging of the specimen as it passes the imaging integrated circuit.
- Such a fluid flow system can comprise a simple system for liquid specimen placement and removal, such as a droplet of a specimen manually applied to the imaging integrated circuit, and a blotting paper oblique to the imaging integrated circuit and in contact with the specimen so as to soak up the liquid over time.
- a fluid flow system comprises a pump or other appropriate means for pulling/pushing the specimen; and a specimen-containing conduit, at least a segment of which (namely, the segment in the optical path) is substantially transmissive to a predetermined wavelength.
- Images of the specimen can be obtained in the presence of the light source 161.
- the light source 161 produces at least one wavelength for which the imaging integrated circuit 1 13 is responsive.
- the light source includes a laser and the predetermined wavelength is the substantially monochromatic wavelength of the laser.
- the light source includes a blackbody and the
- the predetermined wavelength band is a segment of the electromagnetic spectrum which the blackbody is suitably efficient at producing, with or without use of a bandpass spectral filter interposed between the light source and the specimen.
- the light source comprises one or more light-emitting diodes 163, for example, an organic light-emitting diode array, oriented so as to produce light in the predetermined wavelength band or bands.
- the light source is continuous.
- the light source is pulsed.
- the light source is polarized.
- the light source may be placed on the tip of a nanoscale probe.
- the light source includes any ambient, incandescent, or fluorescent light source, including light produced by the sun 165.
- the light source is structured, such as a periodic grating of bright bars. In some embodiments, there may be additional light sources. In conjunction with appropriate oblique, pulsed, polarized, structured, or other forms of illumination, some embodiments can generate additional useful information corresponding to methods known in the art of microscopy, including but by no means limited to dark field, fluorescence, fluorescence lifetime, optical tomography, and polarization microscopy.
- the specimen is itself the light source 161 ; for example through chemi-luminescence, or because the photosensitive array is treated to render it sensitive to radiation emitted by a radioactive specimen.
- the light source is part of a portable electronic device capable of multi- color light emission 167, such as a smartphone.
- the smartphone has a high-intensity organic light-emitting diode display 169 that allows for illumination at different wavelengths and positions relative to the photosensitive surface, with independently controlled onset and duration and capable of simultaneous light source control so as to approximate a uniformly diffuse source.
- the spectra of the light source(s) may lie in any predetermined region of the electromagnetic spectrum detectable using photosensitive arrays, with or without specialized treatments to extend the effective ranges of wavelengths detectable by such arrays.
- the predetermined wavelength or wavelength band is in the infrared spectrum. In some embodiments, the predetermined wavelength or wavelength band is in the ultraviolet spectrum. In some embodiments, the
- predetermined wavelength or wavelength band is in the visible spectrum. In some embodiments, the predetermined wavelength or wavelength band is in the X-ray spectrum. In some embodiments, the predetermined wavelength or wavelength band is in the microwave spectrum. In some embodiments, the predetermined wavelength or wavelength band is approximately that which has a frequency between about 1 Terahertz and about 1 ,000 Terahertz. Combinations of light in two or more bands may be used in some examples.
- the light source includes individually controlled light- emitting diodes (LEDs) selected for their spectral emission characteristics and their uniformity of emitted light, and positioned so as to facilitate the analyses
- LEDs individually controlled light- emitting diodes
- the light sources are positioned so as to uniformly illuminate the specimen chamber.
- the LEDs are controlled, for example, by either an embedded controller incorporated within the instrument or by a
- the microprocessor contained in smartphones or other commercially-available, "off-the- shelf computing devices.
- the LEDs will be controlled, for example, either singly or in groups so as to facilitate the analyses to be contemplated, including but not limited to conventional microscopy wherein the illuminator, the specimen and the imaging system are substantially aligned, and dark-field microscopy wherein the specimen is illuminated from an angle outside the acceptance angle of the pixel.
- the contemplated contact microscope can be used for, but not be limited to, e.g., color imaging, fluorescence microscopy, polarization microscopy, infra-red and ultra-violet microscopy.
- Some embodiments will incorporate multiple illuminators, each of which may have different characteristics so as to facilitate the conduct of a wider range of analyses.
- the illuminators will be easily interchangeable.
- the illuminators may include organic LED (OLED) or active matrix organic LED
- an AMOLED panel with selective addressing. Some embodiments facilitate both uniform specimen illumination and rapid illumination variation so as to facilitate analyses yet to be contemplated with both stationary and moving specimens.
- an AMOLED panel may be used to illuminate the specimen through appropriate control of the panel photoemitters.
- the illuminator can include LEDs, organic LED panels, fluorescent panels, x-ray sources, ultraviolet sources, ambient illumination such as sunlight or room light, incandescent sources, or any other light source, including none, e.g., for chemiluminescent specimens, and combinations of these examples.
- Configurations of the sources include, but are not limited to, flat panels, rectangular or other grid layouts of sources, movable sources, multi-color sources, and sources affixed to the inside or a hemispherical shell mounted over the specimen chamber with the centre of the chamber as the center of the shell, or combinations of them.
- Control of the illumination sources may include, but not be limited to, steady illumination, selectively exciting one or a plurality of illumination sources simultaneously or in sequence, controlling the intensity of any one or a plurality of sources, controlling each or a plurality of sources so as to have a specific temporal illumination pattern, or using any one or any combination of them and others (including future technologies) .
- the controller for the illumination may include, but not be limited to, a manual controller such as a switch or knob, an automated embedded computing system, an external computing system such as a smartphone, an external computing system such as a desktop or laptop computer, or a combination of the foregoing.
- FIG. 7 illustrates features of some embodiments.
- the imaging device 400 is placed in a housing 401 with a hinged lid, by which hinge dry specimens may be inserted and removed.
- an organic LED light source 461 illuminates the specimen.
- Integral to the lid and bonded to the light source 461 is the circuitry 495 for input output and illumination control.
- Power connector 458 is attached to the circuitry 495.
- Input/output connector 456, preferably a USB interface, is attached to the circuitry 495 adjacent to the light source 461.
- Paired fluid flow connectors 452, 454 attach to a fluid flow system akin to that in FIG. 4.
- the form factor of the entire embodiment of FIG. 7 can be about that of a smartphone, for example.
- FIG. 8 illustrates the flow of light and output data when an embodiment of an imaging system is in operation.
- a light source 361 produces light in, for example, a predetermined wavelength or wavelength band.
- a collimator 393 having a lens, filter, or combination thereof ensures that the light is collimated along an optical path and is composed of substantially only wavelengths of the predetermined wavelength or wavelength band.
- Light travels along the optical path toward the imaging integrated circuit 313.
- the angle of incidence of the light onto the imaging integrated circuit will be oblique, rather than normal.
- an optional cover 307 substantially transmissive to the
- an optional coating 380 lies between the specimen and the imaging integrated circuit 313.
- the resultant image as captured by the imaging integrated circuit 313 is outputted to a computer-based system 395 for storage, readout, or analysis.
- high-resolution refers, for example, to a resolution that equals or exceeds the resolution of standard lens-based optical microscopes.
- high-resolution can mean less than 5 ⁇ , less than 2 ⁇ , less than 1 ⁇ , less than about 0.5 ⁇ , or even less.
- Resolution is primarily determined by the pixel size of the photosensitive array. Some photosensitive arrays have many million square pixels each slightly more than 1 ⁇ on a side, resulting in a resolution of about 1 ⁇ ; the resolution achievable will improve with decreasing pixel sizes, theoretically exceeding, for example, 1 billion pixels, each as small as 200 nm or less on a side, as the design and fabrication techniques of integrated circuits or other devices improve.
- the number, shape, and arrangement of pixels in the array is arbitrary, with no intrinsic limit, and can be predetermined for manufacture based on the corresponding application of interest.
- the longest pixel dimension is 10 ⁇ or smaller. In some embodiments, the longest pixel dimension is 5 ⁇ or smaller. In some embodiments, the longest pixel dimension is 1 micron or smaller. In some embodiments, the longest pixel dimension is 500 nm or smaller. In some embodiments, the longest pixel dimension is 250 nm or smaller.
- Imaging integrated circuits can be constructed that have pixel sizes smaller than the wavelength of visible light, as shown, for example, in United States patent 7,153,720, incorporated here by reference.
- the imaging integrated circuit includes a charge-coupled device (CCD).
- the imaging integrated circuit is fabricated using complementary metal-oxide
- CCDs have advantages for contact optical microscopy applications, including the ability to detect light over the full exposed surface of the chip (100% fill factor), though they have slower readout speeds relative to CMOS due to requirement for sequential transfer of charge from light-sensing
- full-frame architecture is desirable to maximize the proportion of the chip available for imaging, but requires an external shutter to prevent image smearing during readout; whereas frame-transfer architecture avoids image smearing, but in the process requires a masked, non-photosensitive area of the parallel register of about the same size as the photosensitive area of the parallel register, with the result that the imaging integrated circuit has about half the photosensitive area of a full-frame architecture. Because of the small area of the individual pixels in the arrays used in this invention, the charge collected in each pixel will be small under many imaging conditions;
- CCDs of any architecture may additionally employ electron multiplying gain, in which high clock voltages applied to an extended region of the serial register(s) amplify the charge of each pixel as it is shifted to the output node(s).
- CMOS devices have alternative advantages for these applications, including less expensive fabrication, signal processing by electronic elements embedded in individual pixels, and the ability to read out independently-addressed pixel values individually without sequential transfer.
- thinned back-side illuminated arrays are used; though previously requiring expensive and complex fabrication methods, these can now be fabricated cheaply using bonded wafer processes such as those that use silicon-on-insulator substrates with a buried oxide layer as an etch-stop to yield a uniformly optimally thinned light-absorbing back layer (see as an example, U.S. Patent No. 7,425,460, incorporated here by reference).
- Light entering ordinary (front-side illuminated) imaging integrated circuits typically passes through overlying layers that scatter light and whose metal circuit elements block the underlying photosensitive layer; in back-side illuminated imaging integrated circuits the photosensitive layer is close to the surface, above the metal circuit-bearing layers, typically resulting in less light blocking (larger "fill factors”) and consequently higher effective quantum efficiency.
- the imaging integrated circuit is windowless.
- Most commercially available imaging devices have a protective window over the CCD or CMOS, and typically this window must be absent in order for the specimen to come close enough to the photosensitive surface to achieve high resolution, as defined above, without computational image processing.
- resolution is determined by the pixel size or, more precisely, by the size of a circle of equivalent area (i.e., -450 nm resolution for a 400nm x 400 nm pixel), although resolution may be further enhanced by computation, specimen flow, or other means. No lenses or any other optical components are required to achieve these conditions, and thus to achieve such pixel-limited resolution.
- the transmission coefficients are:
- T T ° + Tp
- T s is the resultant transmission coefficient for s-polarized light
- T p is the resultant transmission coefficient for p-polarized light
- T is the resultant transmission coefficient for unpolanzed light.
- the transmission coefficients are plotted in Fig. 10(a) for angles between zero and ninety degrees. From the figure it is seen that about 75 percent of unpolarized light is transmitted up to angles of about 60 degrees, after which point transmission falls off sharply.
- the pixel poses a decreasing profile with respect to the light source.
- a point source of light 703 is positioned above the center of a pixel 713 that is part of a photosensitive array having pixels 701 that constitutes the photosensitive part of an imaging VLSI circuit 705.
- the center of the pixel 713 under the point light source 703 is the point of the
- the light emitted from said point source is emitted in all directions equally.
- the light that falls on the pixel 713 immediately under said point light source receives an amount of light that is proportional to an angle 707 subtended by the area of the pixel at the said point light source.
- the light received by any other pixel in the array, e.g., pixel 717 is proportional to an angle 71 1 that it subtends at the said point light source.
- the angle subtended at the point light source is a function of the pixel area projected toward the point light source and the distance from the point light source to said pixel.
- the projection of the pixel area in the direction of the source is:
- a Treat mn
- d is the distance of the point source above the photosensitive surface
- m and n are the x and y dimensions of each pixel respectively
- r is the distance from the point along the photosensitive surface to the pixel of interest. This projected area subtends a solid angle at the source given by: mnd
- the distance between the specimen and the photosensitive surface is approximately equal to one of the following quantities: ten times the average wavelength produced by the light source, or less than five times the average wavelength, or preferably less than three times the average wavelength, or more preferably less than the predetermined wavelength, or still more preferably less than half the predetermined wavelength.
- the supporting circuitry for readout is contained within the imaging integrated circuit.
- the supporting circuitry is coupled to additional supporting circuitry or microprocessors that control the functions of the integrated circuit, such as gain or data clock rate.
- the imaging integrated circuit is commercial and off-the-shelf, having a high-resolution photosensitive array, supporting circuitry for readout, and an industry-standard interface for connection to a computer-based system for image data display, storage, and analysis, for example, the Aptina MT9E013, the OmniVision OV14825, and the OmniVision OV14810; the technical data for which are incorporated here by reference.
- the OmniVision OV5642 incorporates the full functionality of a single chip, 5 megapixel digital camera with 1.4 micron pixel widths, including output of images at 15 frames per second (fps) in RAW RGB mode and up to 60 fps in 1080i resolution.
- the OV5642 supplies images for readout via serial camera control bus (SCCB) and mobile industry processor (MIPI) interfaces using digital video parallel and MIPI serial ports. It also supports output in RGB565/855/444, CCIR656, YUV422/420, and YCbCr422 modes.
- SCCB serial camera control bus
- MIPI mobile industry processor
- Computer-based systems that are capable of connection to the supporting circuitry may be embedded or standalone, purpose-built or off-the-shelf, including, for example purpose-designed embedded computing systems, smartphones, portable computers, and netbooks.
- the computer-based system has firmware or software for image analysis, storage, illumination control, and display. Such firmware or software has previously been paired with optical microscopes and digital camera technology.
- the computer-based system implements algorithms to enhance, detect, analyze, characterize, and measure images of cells and other specimens of interest and to display or transmit the result of these algorithms to a human operator and/or a second computer-based system, such as a smartphone or storage system including hospital record storage systems.
- the computer-based system implements enhancement algorithms that can identify images of discrete specimens in smooth flow in a series of time-lapsed images.
- the imaging integrated circuit's supporting circuitry is coupled to additional circuitry on the mounting block.
- the mounting block incorporates certain interfaces in hardware that are capable of supplying the RAW, RGB, and/or TWAIN standard. Examples of interfaces for optical microscope cameras that could be adapted include those included in the Jenoptik ProgRes Professional Color CCD Firewire Camera; the Luminera Infinity Color CCD or CMOS USB-2 Cameras; and the Motic Moticam Color CMOS USB-2 Camera; the technical data and owner's manuals for which are incorporated here by reference.
- a computer-based system is coupled to the mounting block interfaces for imaging analysis, display, and storage.
- the image captured by the imaging integrated circuit is outputted to a storage medium.
- the image captured by the imaging integrated circuit is outputted to a real-time display device.
- only pixels of interest need be output from the imaging integrated circuit in order to maintain a desired high temporal resolution; CMOS-based imaging integrated circuits are well suited for this task but other architectures are possible.
- the raw data of pixel array intensities, or the post-acquisition images themselves, may be enhanced by various computational means including but not limited to deconvolution, pixel interpolation, spatial filtering, noise reduction, edge enhancement, and other methods.
- a suboptimal point- spread function (whereby light meant to be detected at a given pixel is also detected by an adjacent pixel) may be corrected computationally.
- the imaging integrated circuit, associated electronics, and analysis device are integrated so as to be combined in a portable housing; the light source may be integrated, standalone, or supplied from ambient light, allowing for desktop-, laptop- , cellphone-, or smaller-sized microscopes as the desired application requires.
- a chamber lid that is substantially transmissive to at least one wavelength of light produced by a light source.
- the locating block is preferably a rectangle.
- the walls of the chamber lid may be square, rectangular, circular, elliptical, or some other shape appropriate to the specimen being imaged.
- the top surface of the chamber lid is absent and a multi-colour light-emitting display surface forms the top of the specimen chamber.
- the chamber lid and locator block are partially or substantially transparent or translucent. In other embodiments, the chamber lid and locator block are opaque; examples of applications for such a design include chemiluminescence imaging and autoradiography.
- the specimen chamber lid is not present, as for microscopic imaging of the surface of large or thick specimens.
- the specimen chamber has a probe; examples of probes include temperature probe 501 and pH probe 503.
- the specimen chamber has a pair or more of mounted electrodes 507, 509 along the perimeter of the chamber for applying transverse or longitudinal electric fields or for stimulation of specimens. Such an arrangement of electrodes may be used, as examples and in conjunction with appropriate fluid handling as described above, for electrophoresis, separation/sorting, determination of specimen surface charge, determination of zeta potential, cell stimulation, and specimen orientation.
- the specimen chamber has a heating element 505. Such a heating element may be used, as examples, in the observation of time-dependent processes and in the incubation of live specimens for time-lapse imaging.
- the photosensitive surface has been treated with one or more thin layers.
- the layers may be considered thin when the aggregate thickness of such layers as applied to a photosensitive surface still allows for the near-field criterion to be satisfied or approximately satisfied.
- the layers are thin enough for specimens to come within half a pixel width of the photosensitive surface.
- the layers are thin enough in the direction of the optical path so that the total distance that the optical path takes through the layers is no more than about the wavelength of interest.
- a thin layer of transparent chemically resistant material coats the photosensitive surface.
- Such a thin-film substrate may be any sufficiently transparent and insulating material, including but not limited to silicon oxide, titanium oxide, aluminum oxide, tantalum oxide, magnesium fluoride, lanthanum fluoride, aluminum fluoride, silicon nitride, and silicon oxynitride; and it may be deposited by a variety of means including but not limited to magnetron sputtering, chemical vapour deposition, thermal or vacuum arc plasma evaporation.
- the substrate is a dielectric thin film acting as an interference filter, thereby restricting the spectral sensitivity of the underlying pixels as appropriate to a given application.
- the substrate is used to effect certain forms of color imaging.
- the substrate is substantially transmissive to a portion of a predetermined wavelength band, such as a band-pass filter.
- the substrate 618 is substantially transmissive to an alternative predetermined wavelength band which corresponds to the wavelength band produced by fluorescence, emission, or in other ways, of the specimen.
- the substrate includes a dielectric thin film acting as an anti-reflection coating.
- the photosensitive surface is silanized so as to decrease adhesion between the surface and the specimen.
- the chemically resistant material 615 includes diamond, deposited in a suitably thin layer as, for example, by chemical vapor deposition.
- the chemically resistant material includes AI2O3 or S13N4, deposited in a suitably thin layer as, for example, by chemical vapour deposition.
- Such materials can impart more robust characteristics to the photosensitive surface, allowing for ease of cleaning as well as protection of the surface from abrasive specimens.
- a passivation layer 620 typically of S13N4, coats the imaging integrated circuit, resulting in reduced conductivity when used with metallic or other conductive samples such as salt solutions. Technology is available to deposit such filters as a thin film and in arbitrary pixel-by-pixel patterns.
- a thin layer of polarizing material 614 coats the photosensitive surface.
- a thin layer of absorptive material 614 coats the photosensitive surface.
- a thin layer of interference material 614 coats the photosensitive surface.
- a thin layer of surface plasmon generating material 619 coats the photosensitive surface.
- a thin layer of adhesive material 617 coats the imaging integrated circuit 613. Coatings with molecules having specific affinities can be used to exclude or enrich particular cells or other specimens of interest. Such treatment could also be used, in conjunction with fluorophores 616, nanoparticles or microbeads, for binding assays.
- Non-selective adhesives will create an imaging "stick patch" that could be used, as an example, for forensic applications.
- a thin layer of light-transmissive material 614 containing fluorophores, phosphors or up- converters coats the photosensitive surface. Such molecules are excited at one wavelength and emit at another.
- fluorophores are excited with wavelengths outside the spectrally sensitive range of the imaging integrated circuit and emitting, including by frequency upconversion, within the circuit's spectral range, thereby extending the useful spectral range of the imaging integrated circuit, e.g. into the X-ray spectrum.
- the device further comprises a system for detecting Raman scattering. In some embodiments, the device further comprises a system for detecting X-ray fluorescence.
- a specimen of a thin Mylar sheet was placed in direct contact with the exposed surface of a commercially available, 1.3 megapixel CMOS imaging integrated circuit having 5.2 ⁇ x 5.2 ⁇ pixels, and an image (Fig. 1 1 ) was collected using a diffuse white light source, a computer, and commercially available image acquisition software.
- the upper left and upper right comers of the field of view are empty, with the specimen filling the rest of the field of view; scratches and other features of the specimen as small as single pixels are clearly visible.
- Example 2 Using the CMOS imaging integrated circuit and light source of Example 1 , a specimen of aerosol organic solvent was nebulized and thereby deposited onto the chip surface. Acquisition of the image produced Fig. 12.
- a ⁇ ⁇ droplet of water was deposited directly onto the CMOS chip surface as in Examples 1 and 2, using the same light source. Edges of the droplet spontaneously aligned with the pixel rows and columns, yielding the unusual lozenge shape.
- the protective window of an Aptina CMOS imaging integrated circuit was removed, exposing the photosensitive surface of the array having of 2.2 ⁇ x 2.2 ⁇ pixels.
- a diffuse white light source was used, as was a computer-based system equipped with commercially available software for image acquisition as supplied with the array.
- a minute sample ( ⁇ 10 ⁇ 1) of blood was obtained from an African clawed frog (Xenopus laevis) and diluted in calcium-free amphibian Ringer's solution. A drop of the diluted blood was deposited directly onto the surface of the array. Acquisition of an image by the array produced Fig.
Abstract
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US25578109P | 2009-10-28 | 2009-10-28 | |
PCT/US2010/054240 WO2011053631A1 (fr) | 2009-10-28 | 2010-10-27 | Imagerie de microscopie |
Publications (3)
Publication Number | Publication Date |
---|---|
EP2494400A1 true EP2494400A1 (fr) | 2012-09-05 |
EP2494400A4 EP2494400A4 (fr) | 2017-12-13 |
EP2494400B1 EP2494400B1 (fr) | 2021-12-08 |
Family
ID=43898090
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP10827423.4A Active EP2494400B1 (fr) | 2009-10-28 | 2010-10-27 | Imagerie de microscopie |
Country Status (6)
Country | Link |
---|---|
US (8) | US9041790B2 (fr) |
EP (1) | EP2494400B1 (fr) |
JP (4) | JP2013509618A (fr) |
CN (2) | CN102713720B (fr) |
CA (1) | CA2778725C (fr) |
WO (1) | WO2011053631A1 (fr) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9041790B2 (en) | 2009-10-28 | 2015-05-26 | Alentic Microscience Inc. | Microscopy imaging |
US9075225B2 (en) | 2009-10-28 | 2015-07-07 | Alentic Microscience Inc. | Microscopy imaging |
US9989750B2 (en) | 2013-06-26 | 2018-06-05 | Alentic Microscience Inc. | Sample processing improvements for microscopy |
US10502666B2 (en) | 2013-02-06 | 2019-12-10 | Alentic Microscience Inc. | Sample processing improvements for quantitative microscopy |
Families Citing this family (57)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20120044341A1 (en) * | 2010-08-19 | 2012-02-23 | Stith Curtis W | Optofluidic microscope system-on-chip |
CN103262203B (zh) | 2011-03-03 | 2016-01-20 | 加州理工学院 | E-petri培养皿、设备和系统 |
US20140160236A1 (en) * | 2011-07-29 | 2014-06-12 | The Regents Of The University Of California | Lensfree holographic microscopy using wetting films |
US10509976B2 (en) | 2012-06-22 | 2019-12-17 | Malvern Panalytical Limited | Heterogeneous fluid sample characterization |
EP2864759A2 (fr) * | 2012-06-22 | 2015-04-29 | Malvern Instruments Ltd | Caractérisation de particules |
WO2014025037A1 (fr) | 2012-08-10 | 2014-02-13 | 浜松ホトニクス株式会社 | Elément à diffusion raman exaltée par effet de surface, et son procédé de production |
WO2014025035A1 (fr) | 2012-08-10 | 2014-02-13 | 浜松ホトニクス株式会社 | Elément à diffusion raman exaltée par effet de surface |
JP6230250B2 (ja) * | 2013-03-29 | 2017-11-15 | 浜松ホトニクス株式会社 | 表面増強ラマン散乱ユニット、及びラマン分光分析方法 |
CA2881823C (fr) * | 2012-08-20 | 2019-06-11 | Illumina, Inc. | Procede et systeme de sequencage reposant sur la duree de vie de fluorescence |
US9778200B2 (en) | 2012-12-18 | 2017-10-03 | Ixensor Co., Ltd. | Method and apparatus for analyte measurement |
CA2938896A1 (fr) * | 2013-02-06 | 2014-08-14 | Alentic Microscience Inc. | Detection et utilisation d'une lumiere representative d'un echantillon |
CA2900842C (fr) | 2013-03-12 | 2020-01-21 | Ventana Medical Systems, Inc. | Microscopie amelioree numeriquement pour histologie multiplexee |
TWI611175B (zh) | 2013-03-29 | 2018-01-11 | Hamamatsu Photonics Kk | 表面增強拉曼散射單元及拉曼分光分析方法 |
KR101941135B1 (ko) * | 2013-07-12 | 2019-01-22 | 나우다이아그노스틱스, 인코포레이티드 | 트랜스-비주얼 감도를 가진 보편적 신속 진단 테스트 판독기 |
US9372292B2 (en) * | 2013-12-13 | 2016-06-21 | Canon Kabushiki Kaisha | Imaging apparatus having light source identification and image quality correction functions and method for controlling imaging apparatus |
JP6545457B2 (ja) * | 2014-03-07 | 2019-07-17 | パナソニック株式会社 | プレパラート、透明プレート、プレパラートの作製方法、スライドガラス、画像撮影装置、画像撮影方法、プレパラート作製装置、およびプレパラート部品セット |
JP6394960B2 (ja) * | 2014-04-25 | 2018-09-26 | パナソニックIpマネジメント株式会社 | 画像形成装置および画像形成方法 |
JP6260871B2 (ja) * | 2014-06-27 | 2018-01-17 | パナソニックIpマネジメント株式会社 | プレパラート部品セット、プレパラート、プレパラートの作製方法、画像撮影装置、および画像撮影方法 |
US20160050376A1 (en) * | 2014-08-18 | 2016-02-18 | Ron Fridental | Image sensor with sub-wavelength resolution |
JP6551835B2 (ja) * | 2014-08-22 | 2019-07-31 | パナソニックIpマネジメント株式会社 | ソケット、アダプタ、および組立治具 |
JP6349202B2 (ja) * | 2014-08-29 | 2018-06-27 | シスメックス株式会社 | 蛍光検出装置、被検物質検出装置、及び蛍光検出方法 |
JP2017212238A (ja) * | 2014-10-10 | 2017-11-30 | パナソニックIpマネジメント株式会社 | 固体撮像装置 |
CN107110772B (zh) * | 2014-11-25 | 2020-05-19 | 松下知识产权经营株式会社 | 电子标本保持部件、及其组装方法 |
WO2016084310A1 (fr) * | 2014-11-27 | 2016-06-02 | パナソニックIpマネジメント株式会社 | Dispositif d'acquisition d'image, système de formation d'image et procédé de formation d'image |
JP2018018840A (ja) * | 2014-12-08 | 2018-02-01 | パナソニックIpマネジメント株式会社 | 固体撮像装置およびその製造方法 |
JP2018018841A (ja) * | 2014-12-08 | 2018-02-01 | パナソニックIpマネジメント株式会社 | 固体撮像装置およびその製造方法 |
CN104597016B (zh) * | 2015-01-16 | 2018-01-16 | 中国科学院昆明动物研究所 | 倒置激光共聚焦显微镜动植物活体观测装置及方法 |
EP3268737A4 (fr) * | 2015-03-10 | 2018-11-14 | Alentic Microscience Inc. | Perfectionnements apportés au traitement d'échantillons pour la microscopie quantitative |
JP2018078130A (ja) * | 2015-03-18 | 2018-05-17 | パナソニックIpマネジメント株式会社 | 固体撮像装置 |
WO2017143332A1 (fr) * | 2016-02-18 | 2017-08-24 | Optofluidics, Inc. | Système et procédé de caractérisation de particules dans un échantillon de fluide |
DK3239689T3 (da) * | 2016-04-26 | 2022-01-10 | Atten2 Advanced Monitoring Tech S L | Fluidovervågningssystem |
KR102603196B1 (ko) * | 2016-11-03 | 2023-11-15 | 엠쥐아이 테크 컴퍼니 엘티디. | 생물학적 또는 화학적 분석을 위한 바이오센서들 및 이를 제조하는 방법 |
KR102535751B1 (ko) | 2017-03-20 | 2023-05-22 | 엠쥐아이 테크 컴퍼니 엘티디. | 생물학적 또는 화학적 분석을 위한 바이오센서 및 그 제조 방법 |
US20190056385A1 (en) | 2017-08-17 | 2019-02-21 | Abbott Point Of Care Inc. | Method of imaging assay beads in a biological sample |
CN110869746B (zh) | 2017-08-17 | 2023-08-11 | 雅培医护站股份有限公司 | 利用通用电路系统执行光学和电化学测定的技术 |
CN110869745B (zh) | 2017-08-17 | 2023-08-11 | 雅培医护站股份有限公司 | 用于执行光学测定的设备、系统和方法 |
EP3669176A1 (fr) | 2017-08-17 | 2020-06-24 | Abbott Point of Care Inc. | Procédé d'imagerie de cellules sanguines |
US20190056384A1 (en) | 2017-08-17 | 2019-02-21 | Abbott Point Of Care Inc. | Single-use test device for imaging assay beads |
US20190054466A1 (en) | 2017-08-17 | 2019-02-21 | Abbott Point Of Care Inc. | Single-use test device for imaging blood cells |
EP3669179B1 (fr) | 2017-08-17 | 2023-07-19 | Abbott Point Of Care Inc | Systèmes pour effectuer des analyses optiques et électrochimiques |
KR102373676B1 (ko) * | 2017-08-21 | 2022-03-15 | 한국광기술원 | 테라헤르츠 센서 및 그 측정 방법 |
WO2019060177A1 (fr) | 2017-09-19 | 2019-03-28 | Complete Genomics, Inc. | Fabrication de cellules de flux de séquençage au niveau de la tranche |
EP3717887A4 (fr) | 2017-11-28 | 2020-10-21 | Alentic Microscience Inc. | Classification de microbilles dans une imagerie en champ proche |
TWI685960B (zh) * | 2018-02-03 | 2020-02-21 | 美商伊路米納有限公司 | 使用感測器的主動表面的結構和方法 |
WO2019170757A2 (fr) * | 2018-03-07 | 2019-09-12 | LIFE TECHNOLOGIES GmbH | Appareils, systèmes et procédés d'imagerie |
CN112740016A (zh) | 2018-09-14 | 2021-04-30 | 亿明达股份有限公司 | 流动池及与其相关的方法 |
US20210396981A1 (en) * | 2018-11-09 | 2021-12-23 | Arizona Board Of Regents On Behalf Of The University Of Arizona | Method and apparatus for confocal microscopes |
US20220091307A1 (en) * | 2018-11-29 | 2022-03-24 | La Trobe University | Microscopy method and system |
EP3906433A4 (fr) * | 2018-12-31 | 2022-09-07 | Arizona Board of Regents on behalf of Arizona State University | Essai de diffusion quantitative améliorée de nanoparticules amplifiables dans un microscope à champ sombre à faible grossissement |
US11195864B2 (en) * | 2019-03-01 | 2021-12-07 | Omnivision Technologies, Inc. | Flip-chip sample imaging devices with self-aligning lid |
US11255850B2 (en) | 2019-03-28 | 2022-02-22 | Alentic Microscience Inc. | Bead-based analysis of a sample |
US11609233B2 (en) | 2019-03-28 | 2023-03-21 | Alentic Microscience Inc. | Indicator-based analysis of a sample |
US11719700B2 (en) | 2019-03-28 | 2023-08-08 | Alentic Microscience Inc. | Upconversion for microscopy |
EP4115230A4 (fr) * | 2020-03-06 | 2023-08-16 | Alentic Microscience Inc. | Dispositif d'imagerie portable |
WO2021224900A2 (fr) * | 2020-05-07 | 2021-11-11 | NewSight Imaging Ltd. | Dispositif et procédé d'analyse spectrale d'un échantillon de composé |
CN111641010A (zh) * | 2020-06-15 | 2020-09-08 | 桂林电子科技大学 | 一种太赫兹波段温控开关器件 |
JP7335011B1 (ja) | 2022-03-28 | 2023-08-29 | 株式会社Iddk | 顕微観察装置及びカートリッジ |
Family Cites Families (214)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3447863A (en) | 1966-07-11 | 1969-06-03 | Sodell Research & Dev Co | Method for preparing a slide for viewing |
US3551023A (en) | 1969-01-17 | 1970-12-29 | Ibm | Pathology specimen processing method and article |
JPS5243790B1 (fr) | 1971-07-26 | 1977-11-01 | ||
US3872738A (en) | 1973-09-24 | 1975-03-25 | Landis Tool Co | Machine tool |
JPS5326077Y2 (fr) | 1973-09-26 | 1978-07-03 | ||
JPS5219937U (fr) | 1975-07-31 | 1977-02-12 | ||
JPS5243790A (en) | 1975-10-03 | 1977-04-06 | Chiyoda Chem Eng & Constr Co Ltd | Method of removing nox |
US4338024A (en) | 1980-05-02 | 1982-07-06 | International Remote Imaging Systems, Inc. | Flow analyzer and system for analysis of fluids with particles |
US4612614A (en) | 1980-09-12 | 1986-09-16 | International Remote Imaging Systems, Inc. | Method of analyzing particles in a fluid sample |
JPS58182267A (ja) | 1982-04-16 | 1983-10-25 | Matsushita Electric Ind Co Ltd | 固体撮像装置 |
JPS5948954A (ja) * | 1982-09-13 | 1984-03-21 | Kyocera Corp | 密着型読み取り装置 |
GB8328979D0 (en) | 1983-10-31 | 1983-11-30 | Bellhouse Brian John | Optical assay |
FR2567063B1 (fr) | 1984-07-03 | 1986-11-21 | Stenay Papeterie | Procede de fabrication d'un rouleau elastique de fibres utilisable comme rouleau de calandre |
GB8427285D0 (en) | 1984-10-29 | 1984-12-05 | Bellhouse Medical Products Ltd | Blood bag |
JPS61145102A (ja) | 1984-12-19 | 1986-07-02 | Tokuyama Soda Co Ltd | 除草剤組成物 |
US5059398A (en) | 1985-07-22 | 1991-10-22 | Drummond Scientific Company | Disposable preselected-volume capillary pipet device |
US4963498A (en) | 1985-08-05 | 1990-10-16 | Biotrack | Capillary flow device |
JPH07117607B2 (ja) | 1986-05-08 | 1995-12-18 | 松下電子工業株式会社 | カラ−固体撮像装置 |
US4744643A (en) | 1987-01-20 | 1988-05-17 | Taylor Howard L | Apparatus for restricting motion of living microscopic organisms during observation under a microscope |
US5223398A (en) | 1987-03-13 | 1993-06-29 | Coulter Corporation | Method for screening cells or formed bodies for enumeration of populations expressing selected characteristics |
JPS63229426A (ja) | 1987-03-18 | 1988-09-26 | Fujitsu Ltd | 半導体装置及び半導体素子間の光配線方法 |
US4882284A (en) | 1987-04-13 | 1989-11-21 | Ortho Pharmaceutical Corporation | Method for quantitating and differentiating white blood cells |
JPS6471172A (en) | 1987-09-11 | 1989-03-16 | Oki Electric Ind Co Ltd | Complete contact type image sensor |
US4950455A (en) | 1987-12-22 | 1990-08-21 | Board Of Regents, University Of Texas System | Apparatus for quantifying components in liquid samples |
DE68922390T2 (de) * | 1988-10-21 | 1995-10-05 | Molecular Devices Corp | Verfahren und apparat zur messung der effekte von zellwirksamen mitteln auf lebende zellen. |
US5124141A (en) | 1990-06-14 | 1992-06-23 | Flow Incorporated | Method for diagnosing malaria |
JPH04316478A (ja) | 1991-04-12 | 1992-11-06 | Nec Corp | 生物試料観察装置、システムおよび方法 |
DE69205067T2 (de) | 1991-06-07 | 1996-03-21 | Kansei Kk | Aufprall-Schutzvorrichtung für Passagiere in einem Kraftfahrzeug oder dergleichen. |
JPH0823264B2 (ja) | 1991-08-28 | 1996-03-06 | 戸田建設株式会社 | シールド掘進機における切羽探知レーダ装置 |
US5218211A (en) | 1991-10-23 | 1993-06-08 | The United States Of America As Represented By The Secretary Of Commerce | System for sampling the sizes, geometrical distribution, and frequency of small particles accumulating on a solid surface |
US5846708A (en) | 1991-11-19 | 1998-12-08 | Massachusetts Institiute Of Technology | Optical and electrical methods and apparatus for molecule detection |
JPH05219937A (ja) * | 1992-02-12 | 1993-08-31 | Nec Corp | 生物試料観察システムおよび方法 |
JP3047597B2 (ja) | 1992-02-27 | 2000-05-29 | 松下電器産業株式会社 | 部品実装方法 |
US5585246A (en) | 1993-02-17 | 1996-12-17 | Biometric Imaging, Inc. | Method for preparing a sample in a scan capillary for immunofluorescent interrogation |
US5389779A (en) | 1993-07-29 | 1995-02-14 | At&T Corp. | Method and apparatus for near-field, scanning, optical microscopy by reflective, optical feedback |
KR100262878B1 (ko) | 1993-10-04 | 2000-08-01 | 포만 제프리 엘 | 근접시야 광학현미경 및 그 측정방법 |
IL112147A (en) | 1994-01-19 | 1999-12-22 | Du Pont | Sample holder and method for automated electrophoresis |
DE4417079C2 (de) | 1994-05-17 | 1998-06-10 | Fraunhofer Ges Forschung | Objektträger zum Beobachten von biologischem Material |
US6297025B1 (en) | 1994-06-13 | 2001-10-02 | Matsushita Electric Industrial Co., Ltd | Measurement of complete electrical waveforms of tissue or cells |
US6259104B1 (en) | 1994-07-15 | 2001-07-10 | Stephen C. Baer | Superresolution in optical microscopy and microlithography |
US5627041A (en) | 1994-09-02 | 1997-05-06 | Biometric Imaging, Inc. | Disposable cartridge for an assay of a biological sample |
DE19512117A1 (de) | 1995-04-04 | 1996-10-10 | Itt Ind Gmbh Deutsche | Meßeinrichtung |
US5605813A (en) | 1995-06-06 | 1997-02-25 | Becton, Dickinson And Company | Culture slide assembly |
JPH0921963A (ja) | 1995-07-10 | 1997-01-21 | Hitachi Ltd | 内視鏡装置 |
US5633972A (en) | 1995-11-29 | 1997-05-27 | Trustees Of Tufts College | Superresolution imaging fiber for subwavelength light energy generation and near-field optical microscopy |
US6399023B1 (en) | 1996-04-16 | 2002-06-04 | Caliper Technologies Corp. | Analytical system and method |
US6387707B1 (en) | 1996-04-25 | 2002-05-14 | Bioarray Solutions | Array Cytometry |
JP3753526B2 (ja) | 1996-12-18 | 2006-03-08 | サクラ精機株式会社 | 顕微鏡標本のカバーガラス貼着方法と装置 |
CA2389358C (fr) | 1996-12-31 | 2008-07-15 | Genometrix Incorporated | Procede et dispositif d'analyse moleculaire multiplexee |
US5880830A (en) | 1997-01-29 | 1999-03-09 | Greenvision Systems Ltd. | Spectral imaging method for on-line analysis of polycyclic aromatic hydrocarbons in aerosols |
JP4169827B2 (ja) | 1997-05-28 | 2008-10-22 | ミクロナス ゲーエムベーハー | 測定装置 |
US5894349A (en) | 1997-08-20 | 1999-04-13 | Lucent Technologies Inc. | Manufacturing method including near-field optical microscopic examination of a semiconductor substrate |
US7030904B2 (en) | 1997-10-06 | 2006-04-18 | Micro-Medical Devices, Inc. | Reduced area imaging device incorporated within wireless endoscopic devices |
EP1054620B1 (fr) | 1998-02-13 | 2010-01-27 | Non-Invasive Technology, Inc. | Examen transabdominal, surveillance et imagerie tissulaires |
US6723290B1 (en) | 1998-03-07 | 2004-04-20 | Levine Robert A | Container for holding biologic fluid for analysis |
US6180314B1 (en) | 1998-05-27 | 2001-01-30 | Becton, Dickinson And Company | Method for preparing thin liquid samples for microscopic analysis |
EP1742058B1 (fr) | 1998-08-28 | 2011-11-30 | febit holding GmbH | Substrats pour procédés de détermination d'analytes et méthodes de fabrication de tels substrats |
JP2000146910A (ja) | 1998-09-02 | 2000-05-26 | Sankyo Co Ltd | 電気泳動システム |
US6441359B1 (en) | 1998-10-20 | 2002-08-27 | The Board Of Trustees Of The Leland Stanford Junior University | Near field optical scanning system employing microfabricated solid immersion lens |
WO2000049392A1 (fr) | 1999-02-17 | 2000-08-24 | Lucid, Inc. | Cassette destinee a faciliter le sectionnement optique d'un prelevement de tissu retenu |
US6690464B1 (en) | 1999-02-19 | 2004-02-10 | Spectral Dimensions, Inc. | High-volume on-line spectroscopic composition testing of manufactured pharmaceutical dosage units |
US6396980B1 (en) | 1999-02-22 | 2002-05-28 | Alliance Fiber Optics Products, Inc. | Multi-port fiber optic device with V-groove dual fiber collimator for WDM application |
WO2000050859A1 (fr) | 1999-02-23 | 2000-08-31 | Teraprobe Limited | Procede et appareil de visualisation dans la bande des terahertz |
EP1041624A1 (fr) | 1999-04-02 | 2000-10-04 | Interuniversitair Microelektronica Centrum Vzw | Methode de transfert de substrates ultra-minces et mis en oeuvre de sa methode dans la fabrication de dispositifs de type couches minces |
US6773676B2 (en) | 1999-04-27 | 2004-08-10 | Agilent Technologies, Inc. | Devices for performing array hybridization assays and methods of using the same |
US6261523B1 (en) | 1999-04-27 | 2001-07-17 | Agilent Technologies Inc. | Adjustable volume sealed chemical-solution-confinement vessel |
JP3127244B2 (ja) * | 1999-04-28 | 2001-01-22 | 鹿児島大学長 | 化学発光in situハイブリダイゼーションと免疫組織化学的染色とを組合わせた二重標識検出法 |
US6621079B1 (en) | 1999-07-02 | 2003-09-16 | University Of Virginia Patent Foundation | Apparatus and method for a near field scanning optical microscope in aqueous solution |
JP2001078175A (ja) | 1999-07-07 | 2001-03-23 | Fuji Photo Film Co Ltd | 蛍光観察装置 |
US6285018B1 (en) | 1999-07-20 | 2001-09-04 | Intevac, Inc. | Electron bombarded active pixel sensor |
US6784982B1 (en) | 1999-11-04 | 2004-08-31 | Regents Of The University Of Minnesota | Direct mapping of DNA chips to detector arrays |
US6867851B2 (en) | 1999-11-04 | 2005-03-15 | Regents Of The University Of Minnesota | Scanning of biological samples |
US6323944B1 (en) | 1999-11-19 | 2001-11-27 | Jobin Yvon, Inc. | Compact spectrofluorometer |
US6221687B1 (en) | 1999-12-23 | 2001-04-24 | Tower Semiconductor Ltd. | Color image sensor with embedded microlens array |
US20060263888A1 (en) | 2000-06-02 | 2006-11-23 | Honeywell International Inc. | Differential white blood count on a disposable card |
DE10033268C2 (de) * | 2000-07-10 | 2002-08-08 | Innovatis Gmbh | Verfahren zur Untersuchung von Zellen in einer Kulturflüssigkeit |
US6844150B2 (en) | 2000-08-24 | 2005-01-18 | The Regents Of The University Of California | Ultrahigh resolution multicolor colocalization of single fluorescent probes |
JP4379758B2 (ja) | 2000-11-13 | 2009-12-09 | 日本分光株式会社 | 近接場顕微鏡 |
US20040004759A1 (en) | 2002-07-08 | 2004-01-08 | Olszak Artur G. | Microscope array for simultaneously imaging multiple objects |
JP2002306509A (ja) | 2001-04-10 | 2002-10-22 | Olympus Optical Co Ltd | 遠隔手術支援システム |
US7151246B2 (en) | 2001-07-06 | 2006-12-19 | Palantyr Research, Llc | Imaging system and methodology |
US20040171076A1 (en) | 2001-12-20 | 2004-09-02 | Dejneka Matthew J. | Detectable micro to nano sized structures, methods of manufacture and use |
EP1495292A4 (fr) | 2001-12-21 | 2012-05-09 | Malvern Instr Inc | Surveillance d'un procede spectrometrique |
US8721565B2 (en) | 2005-08-04 | 2014-05-13 | Dune Medical Devices Ltd. | Device for forming an effective sensor-to-tissue contact |
DE10201463B4 (de) * | 2002-01-16 | 2005-07-21 | Clondiag Chip Technologies Gmbh | Reaktionsgefäß zur Durchführung von Array-Verfahren |
US7524459B2 (en) | 2002-01-24 | 2009-04-28 | California Institute Of Technology In Pasadena | Optoelectronic and microfluidic integration for miniaturized spectroscopic devices |
US7738945B2 (en) | 2002-04-19 | 2010-06-15 | University Of Washington | Method and apparatus for pseudo-projection formation for optical tomography |
US7330305B2 (en) | 2002-04-26 | 2008-02-12 | Optiscan Pty Ltd | Laser scanning confocal microscope with fibre bundle return |
JP4331501B2 (ja) | 2002-06-14 | 2009-09-16 | オリンパス株式会社 | 小型光学ユニット |
US6901086B2 (en) | 2002-10-30 | 2005-05-31 | Chian Chiu Li | Stack-type diode laser device |
JP3799322B2 (ja) * | 2002-11-15 | 2006-07-19 | 株式会社日立グローバルストレージテクノロジーズ | 磁気ディスク装置 |
AU2003294822A1 (en) | 2002-12-09 | 2004-06-30 | Quantum Semiconductor Llc | Cmos image sensor |
JP4474287B2 (ja) | 2002-12-25 | 2010-06-02 | バイオ−ラッド ラボラトリーズ インク | 表面プラズモン共鳴センサー |
US20060000429A1 (en) | 2003-01-08 | 2006-01-05 | Stone Kevin T | Vehicle rooftop engine cooling system |
US7267647B2 (en) | 2003-02-10 | 2007-09-11 | Pentax Corporation | Endoscope |
US7023563B2 (en) | 2003-02-14 | 2006-04-04 | Chian Chiu Li | Interferometric optical imaging and storage devices |
US7009172B2 (en) | 2003-03-06 | 2006-03-07 | Board Of Regents Of The University And Community College System Of Nevada, Reno | Method and apparatus for imaging using continuous non-raster patterns |
US20040219184A1 (en) * | 2003-03-25 | 2004-11-04 | The Regents Of The University Of California | Growth of large patterned arrays of neurons on CCD chips using plasma deposition methods |
US7142571B2 (en) | 2003-05-09 | 2006-11-28 | Chian Chiu Li | Stack-type diode laser device |
WO2004104646A1 (fr) | 2003-05-20 | 2004-12-02 | Kansas State University Research Foundation | Microlentille comportant une matiere a base d'un nitrure du groupe iii |
KR100573621B1 (ko) | 2003-07-18 | 2006-04-25 | 주식회사 디지탈바이오테크놀러지 | 세포 개체수 계수용 장치 및 그 제조방법 |
US7727752B2 (en) | 2003-07-29 | 2010-06-01 | Life Technologies Corporation | Kinase and phosphatase assays |
US7079256B2 (en) | 2003-08-09 | 2006-07-18 | Chian Chiu Li | Interferometric optical apparatus and method for measurements |
US20050048498A1 (en) * | 2003-08-29 | 2005-03-03 | Applera Corporation | Compositions, methods, and kits for assembling probes |
US7651598B2 (en) | 2003-09-05 | 2010-01-26 | University Of Maryland | Arbitrary and simultaneous control of multiple objects in microfluidic systems |
US7423766B1 (en) | 2003-12-17 | 2008-09-09 | Chian Chiu Li | Interferometric optical profiler |
EP1711590B1 (fr) | 2004-01-08 | 2016-12-14 | Dako Denmark A/S | Appareil et methodes de traitement de prelevements biologiques, et reservoir associe |
GB2425833B (en) | 2004-01-19 | 2007-02-21 | David Alexander Crawley | Terahertz Radiation Sensor and Imaging System |
US20050190286A1 (en) | 2004-02-26 | 2005-09-01 | Gregory Kaduchak | Integrated array sensor for real time measurements of biological samples |
EP2977757B1 (fr) | 2004-04-07 | 2017-09-13 | Abbott Laboratories | Chambre jetable pour l'analyse de liquides biologiques |
GB0409572D0 (en) | 2004-04-29 | 2004-06-02 | Univ Sheffield | High resolution imaging |
DE102005052752A1 (de) | 2005-11-04 | 2007-05-10 | Clondiag Chip Technologies Gmbh | Vorrichtung und Verfahren zum Nachweis von molekularen Wechselwirkungen |
DE102005052713A1 (de) | 2005-11-04 | 2007-05-16 | Clondiag Chip Tech Gmbh | Vorrichtung und Verfahren zum Nachweis von molekularen Wechselwirkungen |
US7773227B2 (en) | 2004-06-04 | 2010-08-10 | California Institute Of Technology | Optofluidic microscope device featuring a body comprising a fluid channel and having light transmissive regions |
US7751048B2 (en) | 2004-06-04 | 2010-07-06 | California Institute Of Technology | Optofluidic microscope device |
JP2006003653A (ja) | 2004-06-17 | 2006-01-05 | Olympus Corp | 生体試料観察システム |
KR100633778B1 (ko) * | 2004-06-17 | 2006-10-16 | 삼성전자주식회사 | 휴대용 단말기의 영상 출력 제어 방법, 영상 처리 장치 및이를 가지는 휴대용 단말기 |
EP1774389B1 (fr) | 2004-08-05 | 2014-06-18 | JPK Instruments AG | Dispositif pour recevoir un echantillon d'essai |
US7310151B2 (en) | 2004-08-30 | 2007-12-18 | Chian Chiu Li | Interferometric optical apparatus and method using wavefront division |
US7615808B2 (en) | 2004-09-17 | 2009-11-10 | California Institute Of Technology | Structure for implementation of back-illuminated CMOS or CCD imagers |
US7385175B2 (en) | 2004-09-18 | 2008-06-10 | Chian Chiu Li | Bi-directional optical transmission system and method |
WO2006089342A1 (fr) | 2004-10-18 | 2006-08-31 | Macquarie University | Detection par fluorescence |
JP4424158B2 (ja) | 2004-11-04 | 2010-03-03 | ソニー株式会社 | バイオアッセイ装置とバイオアッセイ方法 |
JP2006153785A (ja) * | 2004-12-01 | 2006-06-15 | Hitachi Ltd | 溶液攪拌装置及び分析システム |
JP5020096B2 (ja) | 2004-12-30 | 2012-09-05 | ギブン イメージング リミテッド | 生体内検査のためのキット |
EP1838205A4 (fr) | 2005-01-21 | 2009-07-15 | Optiscan Pty Ltd | Faisceau de fibres pour endomicroscopie de contact |
US7518731B2 (en) | 2005-02-01 | 2009-04-14 | Chian Chiu Li | Interferometric MOEMS sensor |
US7476787B2 (en) | 2005-02-23 | 2009-01-13 | Stc.Unm | Addressable field enhancement microscopy |
WO2007046845A2 (fr) | 2005-02-28 | 2007-04-26 | The Trustees Of Boston College | Detection electrique de resonances plasmoniques |
US20060217594A1 (en) | 2005-03-24 | 2006-09-28 | Ferguson Gary W | Endoscopy device with removable tip |
US7643952B2 (en) | 2005-04-05 | 2010-01-05 | The Board Of Trustees Of The Leland Stanford Junior University | Optical image processing using minimum phase functions |
EP1710565A1 (fr) | 2005-04-05 | 2006-10-11 | F. Hoffmann-La Roche Ag | Système optique mobile pour diagnostics |
US20060239866A1 (en) | 2005-04-26 | 2006-10-26 | Drummond Scientific Company | Glass safety tube |
EP2453240B1 (fr) | 2005-05-23 | 2016-12-28 | Harald F. Hess | Microscopie optique avec marqueurs optiques phototransformables |
US7466409B2 (en) | 2005-06-08 | 2008-12-16 | California Institute Of Technology | Method and apparatus for CMOS imagers and spectroscopy |
NZ564954A (en) | 2005-06-14 | 2011-02-25 | Protox Therapeutics Inc | Method of treating or preventing benign prostatic hyperplasia using modified pore-forming proteins |
US9354156B2 (en) | 2007-02-08 | 2016-05-31 | Emd Millipore Corporation | Microfluidic particle analysis method, device and system |
US8045002B2 (en) | 2005-07-29 | 2011-10-25 | Mitutoyo Corporation | Systems and methods for controlling strobe illumination |
US7796797B2 (en) | 2005-09-28 | 2010-09-14 | Sysmex Corporation | Apparatus for obtaining an image of a blood cell and method for obtaining an image of a blood cell |
US7731901B2 (en) | 2005-10-19 | 2010-06-08 | Abbott Laboratories | Apparatus and method for performing counts within a biologic fluid sample |
US20090163432A1 (en) | 2005-11-08 | 2009-06-25 | Kansai Technology Licensing Organization Co., Ltd. | Therapeutic Agent for Corneal Diseases |
DE602005003592T2 (de) | 2005-12-05 | 2008-10-23 | Foss Analytical A/S | Vorrichtung und Verfahren für spektrophotometrische Analyse |
CN101400297A (zh) | 2006-03-10 | 2009-04-01 | 哈达斯·莱维 | 使用个人取样器装置进行自动化取样和分析的方法和系统 |
RU2422204C2 (ru) | 2006-03-20 | 2011-06-27 | Конинклейке Филипс Электроникс Н.В. | Платформа система в корпусе для электронно-микрофлюидных устройств |
EP2005155B1 (fr) | 2006-03-24 | 2021-06-30 | Advanced Animal Diagnostics, Inc. | Test de mammite utilisant un ensemble de chambre microfluidique |
GB0606788D0 (en) | 2006-04-03 | 2006-05-10 | Ind Co Ltd | Confocal microscopy |
US7968833B2 (en) | 2006-04-26 | 2011-06-28 | National University Corporation NARA Institute of Science and Technology | Image sensor with optical and electrical measurement functions |
US7768654B2 (en) | 2006-05-02 | 2010-08-03 | California Institute Of Technology | On-chip phase microscope/beam profiler based on differential interference contrast and/or surface plasmon assisted interference |
US8004692B2 (en) | 2006-06-30 | 2011-08-23 | Chian Chiu Li | Optical interferometer and method |
JP4889437B2 (ja) * | 2006-10-16 | 2012-03-07 | オリンパス株式会社 | 微弱光撮像装置 |
CN103497991A (zh) | 2006-11-06 | 2014-01-08 | 科隆迪亚戈有限公司 | 使用结合元件用于分析的装置和方法 |
US20080144899A1 (en) | 2006-11-30 | 2008-06-19 | Manoj Varma | Process for extracting periodic features from images by template matching |
US7719685B2 (en) | 2006-11-30 | 2010-05-18 | Chian Chiu Li | Near-field optical apparatus and method using photodetector array |
JP2008192813A (ja) | 2007-02-05 | 2008-08-21 | Fujifilm Corp | Ccd固体撮像素子 |
EP1967581B1 (fr) | 2007-03-08 | 2016-08-17 | Imec | Procédé compatible CMOS de fabrication des structures de micro-aiguilles |
US8027083B2 (en) | 2007-04-20 | 2011-09-27 | International Business Machines Corporation | Contact microscope using point source illumination |
US8964020B2 (en) | 2007-04-25 | 2015-02-24 | Stc.Unm | Solid-state microscope for selectively imaging a sample |
WO2008136007A2 (fr) | 2007-05-08 | 2008-11-13 | Amihay Halamish | Acquisition de régions d'intérêt à une fréquence de trame élevée |
US20090028463A1 (en) | 2007-07-23 | 2009-01-29 | Putman Matthew C | Unique digital imaging method |
WO2009082523A2 (fr) | 2007-09-26 | 2009-07-02 | Massachusetts Institute Of Technology | Imagerie 3d haute résolution de nanocristaux semiconducteurs simples |
DE602007002925D1 (de) * | 2007-10-31 | 2009-12-03 | Harman Becker Automotive Sys | Getaktete Leistungsschaltung |
US8552705B2 (en) | 2007-11-09 | 2013-10-08 | St-Ericsson Sa | Lower power controller for DC to DC converters |
US7990539B2 (en) | 2008-01-03 | 2011-08-02 | Chian Chiu Li | Sensor and method utilizing multiple optical interferometers |
CN102087197B (zh) | 2009-12-08 | 2014-06-18 | 龚维燕 | 全功能血液分析仪器中库尔特微孔的共轴照明方法及其分析仪器 |
US8120783B2 (en) | 2008-02-04 | 2012-02-21 | Chian Chiu Li | Biosensing apparatus and method using optical interference |
US8325988B2 (en) | 2008-03-03 | 2012-12-04 | California Institute Of Technology | Image reconstruction by position and motion tracking |
WO2009111577A1 (fr) | 2008-03-04 | 2009-09-11 | California Institute Of Technology | Procédés d’utilisation de dispositifs à microscope optofluidique |
EP2252909A4 (fr) | 2008-03-04 | 2013-03-13 | California Inst Of Techn | Dispositif de microscope optofluidique a reseau de photocapteurs |
US8089630B2 (en) | 2008-03-14 | 2012-01-03 | The Board Of Trustees Of The University Of Illinois | Spectral near-field optical tomography |
CN102027368B (zh) | 2008-03-21 | 2014-02-26 | 艾博特健康公司 | 利用红细胞内含有的血红蛋白的本征色素沉着来确定血样的红细胞指数的方法及设备 |
EP2265946B1 (fr) | 2008-03-21 | 2012-08-01 | Abbott Point Of Care, Inc. | Procédé et appareil permettant de déterminer l'hématocrite d'un échantillon de sang au moyen de la pigmentation intrinsèque de l'hémoglobine contenue dans les globules rouges |
EP2269038B1 (fr) | 2008-03-21 | 2016-07-27 | Abbott Point Of Care, Inc. | Procédé d'analyse de cellules individuelles ou de particule dans un échantillon de sang par fluorescence et absorption d'un colorant |
CN101561443B (zh) | 2008-04-15 | 2013-08-21 | 深圳迈瑞生物医疗电子股份有限公司 | 五分类白细胞模拟物粒子、其制备方法以及含该模拟粒子的质控物和校准物 |
US9602777B2 (en) | 2008-04-25 | 2017-03-21 | Roche Diagnostics Hematology, Inc. | Systems and methods for analyzing body fluids |
JP2012515931A (ja) | 2008-04-25 | 2012-07-12 | ウィンケルマン、ジェイムズ | 全血球数及び白血球百分率を決定するシステム及び方法 |
JP2010011814A (ja) | 2008-07-04 | 2010-01-21 | Japan Science & Technology Agency | 培養細胞観察用チャンバー及びその使用 |
JP5056709B2 (ja) | 2008-10-03 | 2012-10-24 | 凸版印刷株式会社 | 固体撮像素子の製造方法 |
US8372726B2 (en) | 2008-10-07 | 2013-02-12 | Mc10, Inc. | Methods and applications of non-planar imaging arrays |
WO2010062654A2 (fr) | 2008-10-28 | 2010-06-03 | Arizona Board Of Regents For And On Behalf Of Arizona State University | Dispositif et procede pour l'etude de fonctions cellulaires et tissulaires |
US8419623B2 (en) | 2009-01-28 | 2013-04-16 | Cani Optical Systems, Llc | Portable endoscope for diverse medical disciplines |
JP5670052B2 (ja) | 2009-03-26 | 2015-02-18 | シスメックス株式会社 | 血液分析装置、血液分析方法及びコンピュータプログラム |
KR101565750B1 (ko) | 2009-04-10 | 2015-11-05 | 삼성전자 주식회사 | 고감도 이미지 센서 |
US8310022B2 (en) | 2009-06-03 | 2012-11-13 | Sargent Edward H | Photoconductive materials and devices with internal photoconductive gain |
US20120224053A1 (en) | 2009-06-17 | 2012-09-06 | Board Of Regents, The University Of Texas System | Method and apparatus for quantitative microimaging |
JP5219937B2 (ja) | 2009-06-22 | 2013-06-26 | 中国電力株式会社 | 改良土の供試体をキャッピングする方法、及びこの方法に用いる補助具 |
US8570370B2 (en) | 2009-08-31 | 2013-10-29 | Bio-Rad Laboratories, Inc. | Compact automated cell counter |
JP5657673B2 (ja) | 2009-09-16 | 2015-01-21 | メディグス リミテッド | 小径ビデオカメラヘッドおよび可視化プローブおよびそれらを組み込んだ医療機器 |
ES2679269T3 (es) | 2009-09-29 | 2018-08-23 | Research Triangle Institute | Fotodetectores basados en la unión quantum dot-fullerene |
FR2951542B1 (fr) | 2009-10-16 | 2011-12-02 | Commissariat Energie Atomique | Procede de detection optique d'objets micrometriques en solution |
WO2011049965A1 (fr) | 2009-10-20 | 2011-04-28 | The Regents Of The University Of California | Cellule holographique incohérente sans lentille et microscopie sur une puce |
CN102713720B (zh) | 2009-10-28 | 2016-05-11 | 阿兰蒂克微科学股份有限公司 | 显微成像装置和显微成像方法 |
US9075225B2 (en) | 2009-10-28 | 2015-07-07 | Alentic Microscience Inc. | Microscopy imaging |
US20140152801A1 (en) | 2009-10-28 | 2014-06-05 | Alentic Microscience Inc. | Detecting and Using Light Representative of a Sample |
IN2012DN03245A (fr) | 2009-11-13 | 2015-10-23 | Ventana Med Syst Inc | |
US8748186B2 (en) | 2009-12-22 | 2014-06-10 | Abbott Laboratories | Method for performing a blood count and determining the morphology of a blood smear |
US8837803B2 (en) | 2009-12-31 | 2014-09-16 | Abbott Point Of Care, Inc. | Method and apparatus for determining mean cell volume of red blood cells |
US9743020B2 (en) | 2010-03-23 | 2017-08-22 | California Institute Of Technology | Super resolution optofluidic microscopes for 2D and 3D imaging |
ES2905560T3 (es) | 2010-08-05 | 2022-04-11 | Abbott Point Of Care Inc | Método y aparato para análisis automáticos de muestras de sangre completa a partir de imágenes microscópicas |
US9643184B2 (en) | 2010-10-26 | 2017-05-09 | California Institute Of Technology | e-Petri dishes, devices, and systems having a light detector for sampling a sequence of sub-pixel shifted projection images |
EP2661603A4 (fr) | 2011-01-06 | 2014-07-23 | Univ California | Dispositifs et procédés d'imagerie tomographique sans lentille |
EP3904859B1 (fr) | 2011-04-15 | 2023-08-30 | Roche Diagnostics Hematology, Inc. | Système et procédé pour la determination du volume d'une plaquette d'un échantillon de sang, programme informatique et support lisible par ordinateur |
CA2839531A1 (fr) | 2011-06-17 | 2012-12-20 | Constitution Medical, Inc. | Systemes et procedes d'affichage et de re-visualisation d'echantillon |
DE102011117228A1 (de) | 2011-10-28 | 2013-05-02 | Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. | Mikroskopiesystem zur Zustandsbestimmung von Zellen |
BR112014011935B1 (pt) | 2011-11-16 | 2020-11-03 | Leica Biosystems Melbourne Pty Ltd. | elemento de cobertura, método e módulo de tratamento para tratar uma amostra biológica sobre um substrato |
DE102012101377B4 (de) | 2012-02-21 | 2017-02-09 | Leica Biosystems Nussloch Gmbh | Verfahren bei der Vorbereitung von Proben zum Mikroskopieren und Vorrichtung zum Überprüfen der Eindeckqualität von Proben |
FR2987922B1 (fr) | 2012-03-06 | 2014-04-18 | Commissariat Energie Atomique | Procede et dispositif de comptage d'objets |
US20140002662A1 (en) | 2012-06-22 | 2014-01-02 | E. Neil Lewis | Particle characterization |
CA2938896A1 (fr) | 2013-02-06 | 2014-08-14 | Alentic Microscience Inc. | Detection et utilisation d'une lumiere representative d'un echantillon |
US10502666B2 (en) | 2013-02-06 | 2019-12-10 | Alentic Microscience Inc. | Sample processing improvements for quantitative microscopy |
US9304280B2 (en) | 2013-03-14 | 2016-04-05 | The Regents Of The University Of Michigan | Compact lens system and array |
CA3080335C (fr) | 2013-06-26 | 2023-06-13 | Alentic Microscience Inc. | Ameliorations de traitement d'echantillon destinees a la microscopie |
CA3036385C (fr) | 2013-12-17 | 2022-06-21 | Alentic Microscience Inc. | Dosimetres incluant des systemes imageurs sans lentille |
EP3268737A4 (fr) | 2015-03-10 | 2018-11-14 | Alentic Microscience Inc. | Perfectionnements apportés au traitement d'échantillons pour la microscopie quantitative |
HUE043452T2 (hu) | 2016-12-22 | 2019-08-28 | Urban Software Inst Gmbh | Számítógépes rendszer és eljárás megbízható jármûvezérlõ utasítások meghatározására |
-
2010
- 2010-10-27 CN CN201080059753.XA patent/CN102713720B/zh active Active
- 2010-10-27 WO PCT/US2010/054240 patent/WO2011053631A1/fr active Application Filing
- 2010-10-27 CA CA2778725A patent/CA2778725C/fr active Active
- 2010-10-27 US US12/913,639 patent/US9041790B2/en active Active
- 2010-10-27 JP JP2012536989A patent/JP2013509618A/ja active Pending
- 2010-10-27 CN CN201610217300.4A patent/CN105974571B/zh active Active
- 2010-10-27 EP EP10827423.4A patent/EP2494400B1/fr active Active
-
2015
- 2015-04-28 US US14/698,532 patent/US9720217B2/en active Active
- 2015-07-01 JP JP2015132271A patent/JP2015215624A/ja active Pending
-
2017
- 2017-07-06 US US15/642,434 patent/US10114203B2/en active Active
- 2017-10-13 JP JP2017199014A patent/JP2018028683A/ja not_active Withdrawn
-
2018
- 2018-08-27 US US16/113,578 patent/US10345564B2/en active Active
-
2019
- 2019-06-12 US US16/439,333 patent/US10520711B2/en active Active
- 2019-12-02 US US16/701,078 patent/US10866395B2/en active Active
-
2020
- 2020-05-07 JP JP2020081897A patent/JP2020129141A/ja active Pending
- 2020-10-30 US US17/085,389 patent/US11294160B2/en active Active
-
2022
- 2022-04-04 US US17/712,959 patent/US11947096B2/en active Active
Non-Patent Citations (1)
Title |
---|
See references of WO2011053631A1 * |
Cited By (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11294160B2 (en) | 2009-10-28 | 2022-04-05 | Alentic Microscience Inc. | Microscopy imaging |
US11635447B2 (en) | 2009-10-28 | 2023-04-25 | Alentic Microscience Inc. | Microscopy imaging |
US9720217B2 (en) | 2009-10-28 | 2017-08-01 | Alentic Microscience Inc. | Microscopy imaging |
US10520711B2 (en) | 2009-10-28 | 2019-12-31 | Alentic Microscience Inc. | Microscopy imaging |
US10114203B2 (en) | 2009-10-28 | 2018-10-30 | Alentic Microscience Inc. | Microscopy imaging |
US10345564B2 (en) | 2009-10-28 | 2019-07-09 | Alentic Microscience Inc. | Microscopy imaging |
US10620234B2 (en) | 2009-10-28 | 2020-04-14 | Alentic Microscience Inc. | Microscopy imaging |
US9041790B2 (en) | 2009-10-28 | 2015-05-26 | Alentic Microscience Inc. | Microscopy imaging |
US11947096B2 (en) | 2009-10-28 | 2024-04-02 | Alentic Microscience Inc. | Microscopy imaging |
US9075225B2 (en) | 2009-10-28 | 2015-07-07 | Alentic Microscience Inc. | Microscopy imaging |
US10900999B2 (en) | 2009-10-28 | 2021-01-26 | Alentic Microscience Inc. | Microscopy imaging |
US10866395B2 (en) | 2009-10-28 | 2020-12-15 | Alentic Microscience Inc. | Microscopy imaging |
US10768078B2 (en) | 2013-02-06 | 2020-09-08 | Alentic Microscience Inc. | Sample processing improvements for quantitative microscopy |
US10502666B2 (en) | 2013-02-06 | 2019-12-10 | Alentic Microscience Inc. | Sample processing improvements for quantitative microscopy |
US11598699B2 (en) | 2013-02-06 | 2023-03-07 | Alentic Microscience Inc. | Sample processing improvements for quantitative microscopy |
US10809512B2 (en) | 2013-06-26 | 2020-10-20 | Alentic Microscience Inc. | Sample processing improvements for microscopy |
US10746979B2 (en) | 2013-06-26 | 2020-08-18 | Alentic Microscience Inc. | Sample processing improvements for microscopy |
US10459213B2 (en) | 2013-06-26 | 2019-10-29 | Alentic Microscience Inc. | Sample processing improvements for microscopy |
US11874452B2 (en) | 2013-06-26 | 2024-01-16 | Alentic Microscience Inc. | Sample processing improvements for microscopy |
US9989750B2 (en) | 2013-06-26 | 2018-06-05 | Alentic Microscience Inc. | Sample processing improvements for microscopy |
Also Published As
Publication number | Publication date |
---|---|
US20220404600A1 (en) | 2022-12-22 |
US11947096B2 (en) | 2024-04-02 |
CN102713720B (zh) | 2016-05-11 |
CN105974571A (zh) | 2016-09-28 |
EP2494400A4 (fr) | 2017-12-13 |
US20150241679A1 (en) | 2015-08-27 |
US9720217B2 (en) | 2017-08-01 |
WO2011053631A1 (fr) | 2011-05-05 |
US9041790B2 (en) | 2015-05-26 |
CA2778725C (fr) | 2019-04-30 |
US20200174238A1 (en) | 2020-06-04 |
US10520711B2 (en) | 2019-12-31 |
US20170322402A1 (en) | 2017-11-09 |
US11294160B2 (en) | 2022-04-05 |
CN102713720A (zh) | 2012-10-03 |
US20190324239A1 (en) | 2019-10-24 |
JP2015215624A (ja) | 2015-12-03 |
US10345564B2 (en) | 2019-07-09 |
US20110096157A1 (en) | 2011-04-28 |
EP2494400B1 (fr) | 2021-12-08 |
US20210063713A1 (en) | 2021-03-04 |
JP2020129141A (ja) | 2020-08-27 |
US20190094509A1 (en) | 2019-03-28 |
US10866395B2 (en) | 2020-12-15 |
CN105974571B (zh) | 2019-05-28 |
JP2013509618A (ja) | 2013-03-14 |
US10114203B2 (en) | 2018-10-30 |
JP2018028683A (ja) | 2018-02-22 |
CA2778725A1 (fr) | 2011-05-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11947096B2 (en) | Microscopy imaging | |
US11635447B2 (en) | Microscopy imaging | |
US20230164299A1 (en) | Detecting and using light representative of a sample | |
JP7227202B2 (ja) | サンプルを代表する光を検出すること及び利用すること | |
US9683938B2 (en) | Fluorescent imaging using a flatbed scanner |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20120430 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
DAX | Request for extension of the european patent (deleted) | ||
RIC1 | Information provided on ipc code assigned before grant |
Ipc: G02B 21/33 20060101AFI20170706BHEP |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: EXAMINATION IS IN PROGRESS |
|
RA4 | Supplementary search report drawn up and despatched (corrected) |
Effective date: 20171113 |
|
RIC1 | Information provided on ipc code assigned before grant |
Ipc: G02B 21/33 20060101AFI20171107BHEP |
|
17Q | First examination report despatched |
Effective date: 20171211 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: EXAMINATION IS IN PROGRESS |
|
GRAP | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOSNIGR1 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: GRANT OF PATENT IS INTENDED |
|
INTG | Intention to grant announced |
Effective date: 20210510 |
|
GRAS | Grant fee paid |
Free format text: ORIGINAL CODE: EPIDOSNIGR3 |
|
GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE PATENT HAS BEEN GRANTED |
|
AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: FG4D |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: REF Ref document number: 1454215 Country of ref document: AT Kind code of ref document: T Effective date: 20211215 Ref country code: CH Ref legal event code: EP |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R096 Ref document number: 602010067901 Country of ref document: DE |
|
REG | Reference to a national code |
Ref country code: IE Ref legal event code: FG4D |
|
RAP4 | Party data changed (patent owner data changed or rights of a patent transferred) |
Owner name: ALENTIC MICROSCIENCE INC. |
|
REG | Reference to a national code |
Ref country code: LT Ref legal event code: MG9D |
|
REG | Reference to a national code |
Ref country code: NL Ref legal event code: MP Effective date: 20211208 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: RS Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20211208 Ref country code: LT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20211208 Ref country code: FI Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20211208 Ref country code: BG Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20220308 |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: MK05 Ref document number: 1454215 Country of ref document: AT Kind code of ref document: T Effective date: 20211208 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20211208 Ref country code: NO Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20220308 Ref country code: LV Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20211208 Ref country code: HR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20211208 Ref country code: GR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20220309 Ref country code: ES Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20211208 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: NL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20211208 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SM Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20211208 Ref country code: SK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20211208 Ref country code: RO Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20211208 Ref country code: PT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20220408 Ref country code: EE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20211208 Ref country code: CZ Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20211208 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: PL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20211208 Ref country code: AT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20211208 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R097 Ref document number: 602010067901 Country of ref document: DE |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IS Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20220408 |
|
PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: DK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20211208 Ref country code: AL Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20211208 |
|
26N | No opposition filed |
Effective date: 20220909 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SI Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20211208 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: MC Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20211208 Ref country code: IT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20211208 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: DE Payment date: 20230223 Year of fee payment: 13 |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |
|
REG | Reference to a national code |
Ref country code: BE Ref legal event code: MM Effective date: 20221031 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LU Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20221027 |
|
P01 | Opt-out of the competence of the unified patent court (upc) registered |
Effective date: 20230602 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: LI Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20221031 Ref country code: CH Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20221031 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: BE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20221031 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20221027 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: GB Payment date: 20231227 Year of fee payment: 14 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: FR Payment date: 20231227 Year of fee payment: 14 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: HU Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO Effective date: 20101027 |